The present invention relates generally to neurological and psychiatric diseases diagnosed by and/or caused in whole or in part by microRNAs and, more specifically, to the use of individual microRNAs for the diagnosis and treatment of schizophrenia.
Schizophrenia is a chronic, severe and disabling brain disease. Approximately one percent of the population develops schizophrenia during their lifetime—more than two million Americans suffer from the illness in a given year. Schizophrenia typically presents in early adulthood or late adolescence. The illness is characterized by positive symptoms (delusions or hallucinations), negative symptoms (blunted emotions and lack of interest) and disorganized symptoms (confused thinking and speech or disorganized behavior and perception). Additionally, cognitive deficits are also frequently observed, particularly in elderly schizophrenia patients. For some patients, the disorder is life-long, while others may have periodic episodes of psychosis. Men have an earlier age of onset than women, and also tend to experience a more serious form of the illness with more negative symptoms, poorer chances of a full recovery, and a generally worse outcome [Jablensky, 2000]. Systematic reviews show that schizophrenia is 1.4 times more likely to occur in men than in women.
MicroRNAs (miRNAs) are a large family of small, non-coding RNAs that negatively regulate gene expression at the post-transcriptional level [Ambros, 2003; Lai, 2003; Bartel, 2004]. In animals, miRNAs bind to complementary sites in target mRNAs 3′ untranslated regions (UTRs) to create imperfectly paired RNA heteroduplexes that inhibit translation of the target RNAs. Many microRNAs are conserved in sequence and function between distantly related organisms.
miRNAs regulate various biological functions including developmental processes, developmental timing, cell proliferation, neuronal gene expression and cell fate [Klein et al., 2005], apoptosis [reviewed in [Mattick and Makunin, 2005; Croce and Calin, 2005], tissue growth, viral pathogenesis, brain morphogenesis [Giraldez et al., 2005], muscle differentiation [Naguibneva et al., 2006], stem cell division [Hatfield et al., 2005] and progression of human diseases [Ambros, 2003; Palatnik et al., 2003]. Condition-specific, time-specific, and individual-specific levels of gene expression may be due to the interactions of different miRNAs accounting for more accurate genetic expression of various traits [Ying and Lin, 2004].
The large number of miRNA genes, the diverse expression patterns and the abundance of potential miRNA targets suggest that miRNAs may be a significant but unrecognized source of human genetic disease, including neuropsychiatric disorders. A sequence variant in the binding site for the miRNA miR-189 in the SLITRK1 mRNA has been shown to be associated with Tourette's syndrome [Abelson et al., 2005]. In addition, components required for miRNA processing and/or function have also been implicated in fragile X mental retardation [Jin et al., 2004], DiGeorge syndrome [Landthaler et al., 2004] and cancer [Karube et al., 2005], pointing to the wide ranging involvement of miRNAs in disease.
A number of animal models have been developed for schizophrenia, utilizing both non-primate (rat) and primate (monkey) animals. In one commonly used animal model of schizophrenia, phencyclidene (PCP) is chronically administered to the animal subjects, resulting in dysfunctions similar to those seen in schizophrenic humans (Jentsch et al., 1997, Science 277:953 955; Piercey et al., 1988, Life Sci. 43(4):375 385).
The causes of schizophrenia are essentially unknown. Although it is believed to have a genetic component, environmental factors appear to influence the onset and severity of the disease. Neuropathological changes in schizophrenics may include enlargement of the lateral ventricles, cavities in the brain which are part of the cerebrospinal fluid system. Sometimes, there is a decrease in overall brain mass. Several different theories have been developed regarding the etiology of schizophrenia, including the dopaminergic, glutamatergic, and cholinergic theories of schizophrenia. The dopamine hypothesis posits that positive symptoms result from excess function of the neurotransmitter dopamine in the mesolimbic area of the brain. This hypothesis is based largely on indirect, pharmacological evidence that (1) dopamine-antagonizing drugs are effective antipsychotic agents; (2) dopamine-mimicking drug exacerbate schizophrenic symptoms and (3) certain symptoms of acute paranoid schizophrenia can be elicited in non-schizophrenics by amphetamine, a drug that activates dopamine systems. However, negative symptoms have been associated with regionally localized dopamine deficits in the prefrontal cortex. Thus, there is a need for a more effective diagnosis and treatment of this disease. Additionally, there is a need for an earlier detection method for schizophrenia, such as prior to the presentation or onset of noticeable symptoms. The present invention satisfies this need and provides related advantages as well.